L-Glutamate has been identified as the major excitatory transmitter in the mammalian CNS. Recent studies also suggest that in addition to normal neurotransmission, the excitatory amino acid system is also closely tied to an underlying mechanism of neuronal pathology, referred to as excitotoxicity. The excitatory action of L-glutamate is mediated through several different classes of receptors and is terminated by high-affinity transport. Current pharmacological and biochemical evidence suggests that there are at least three distinct receptor classes and two distinct transport systems, all of which can bind L-glutamate. The overall goal of this proposal is to provide an understanding, at the molecular level, of the interactions between L-glutamate and the proteins components (e.g., receptors and transport systems) of the excitatory neurotransmitter system. Although a number of glutamate analogues have been identified that exhibit selectively binding (i.e., kainate, quisqualate, and N-methyl-D-aspartate) there is not a clear understanding of the chemical basis of this selectivity. The fact that such selectivities exist implies the L-glutamate may be binding to each type of receptor in a unique conformation, each of which is mimicked by one of the analogues in some chemically ill-defined way. In order to determine conformation preferences for each receptor type and transport system (i.e., optimal positioning of the functional groups responsible for the binding of agonists or antagonists) an extensive set of conformationally well-defined glutamate analogues will be prepared and biochemically characterized. The results of the structure/activity data, in conjunction with the conformational analysis of the L-glutamate analogues, will provide an understanding of the structural basis of binding selectivity. This data will be of tremendous value in identifying and designing selective probes of the receptors that will eventually allow their respective contributions to excitatory transmission to be individually examined. Furthermore, as imbalances in excitatory transmission are known to produce neuronal degeneration, the identification of antagonists should be of substantial therapeutic value.